Lung cancer is the leading cause of cancer related death. Arising in the bronchial mucosa, squamous cell carcinoma (SCC) is currently difficult to detect early in the disease process. For this reason it is typically well advanced upon discovery providing patients little hope of cure. The research focus of this proposal is to develop and test an accurate screening and assessment tool for the detection and diagnosis of squamous cell carcinoma, and its precursor lesions, in the pulmonary airways. It is hoped that through early detection, diagnosis and consequent treatment the mortality rate associated with the disease can be greatly reduced. This research project is based on a newly developed optical imaging technique termed optical frequency domain imaging (OFDI). OFDI is a noninvasive imaging technology that provides cross-sectional images of biological tissues in resolutions comparable with histopathology. We hypothesize that OFDI will be capable of comprehensively imaging the pulmonary airways at microscopic resolutions and, based on the acquired images, we will be able to accurately differentiate and diagnose SCC and its precursor lesions. During the mentored phase of this award, OFDI diagnostic criteria for the evaluation of bronchial pathology will be established, and a custom OFDI imaging probe will be developed and tested. In the independent phase of the award, an OFDI guided-biopsy paradigm with laser marking will be developed and tested, and a subsequent clinical trial to demonstrate the feasibility of the guided-biopsy paradigm will be conducted. Research training will be a core component of this award proposal during the mentored phase with the primary purpose of providing the candidate with a strong foundation in pulmonary medicine and pathology to supplement her existing expertise in medical imaging and biomedical optics. Training will take place at the Wellman Center for Photomedicine, Massachusetts General Hospital under the mentorship of Drs Guillermo Tearney and Brett Bouma, both considered international authorities in optical diagnostics, and at the Lahey Clinic under the direction of Dr. John Beams, an international leader in interventional pulmonary medicine. This training will be further supplemented with formal coursework at Harvard Medical School, and Massachusetts General Hospital. The training and research contributions supported by this K99/ROO award will serve to establish Dr. Melissa Suter as a successful independent investigator.